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| United States Patent |
5,151,544
|
|
DuPriest
, et al.
|
September 29, 1992
|
Intermediates in the preparation of chiral spirofluorenehydantoins
Abstract
Disclosed is a process for the synthesis of enantiomerically pure R and S
isomers of
2,7-difluoro-4-methoxyspiro[9H-fluorene-9,4-imidazolidene]-2',5'-dione
from 2,7-difluoro-4-methoxyfluorenone. Intermediate amino acid esters and
urea esters and their preparation are also described.
| Inventors:
|
DuPriest; Mark T. (Fort Worth, TX);
Conrow; Raymond E. (Fort Worth, TX);
Kuzmich; Daniel (Fort Worth, TX)
|
| Assignee:
|
Alcon Laboratories, Inc. (Fort Worth, TX)
|
| Appl. No.:
|
530766 |
| Filed:
|
May 25, 1990 |
| Current U.S. Class: |
560/10; 560/34; 560/45; 560/47; 560/48 |
| Intern'l Class: |
C07C 321/00; C07C 229/00 |
| Field of Search: |
560/34,45,10,47,48
|
References Cited
U.S. Patent Documents
| 4117230 | Sep., 1978 | Sarges | 548/309.
|
| 4286098 | Aug., 1981 | Sarges | 548/309.
|
| 4348526 | Sep., 1982 | Sarges | 548/309.
|
| 4419521 | Dec., 1983 | Sarges | 549/404.
|
| 4436745 | Mar., 1984 | York, Jr. | 424/273.
|
| 4438272 | Mar., 1984 | York, Jr. | 548/308.
|
| 4540700 | Sep., 1985 | York, Jr. | 514/278.
|
| 4716113 | Dec., 1987 | Urban | 435/125.
|
| 4864028 | Sep., 1989 | York, Jr. | 546/15.
|
| 4952694 | Aug., 1990 | Brackeen et al. | 546/15.
|
Other References
Sarges, et al., "Synthesis of Optically Active Spirohydantoins by
Asymmetric Induction. Hydantoin Formation from Amino Nitriles and
Chlorosulfonyl Isocyanate", J. Org. Chem:47(21) 4081-4085 (1982).
Okamoto, et al., "Controlled Chiral Recognition of Cellulos
Triphenylcarbamate Derivatives Supported on Silica Gel", J.
Chromatography:363, 173-186(1986).
|
Primary Examiner: Lee; Mary C.
Assistant Examiner: Whittenbaugh; Robert C.
Attorney, Agent or Firm: Brown; Gregg C., Copeland; Barry L.
Claims
We claim:
1. A compound of the formula:
##STR3##
wherein: R=C.sub.1 -C.sub.5 alkyl;
W and X are each, independently of the other, selected from the group
consisting of hydrogen, chloro and fluoro;
one of Y and Z is selected from the group consisting of hydrogen, chloro,
fluoro, methyl, methoxyl and methylthio and the other is selected from the
group consisting of hydrogen, chloro and fluoro;
with the proviso that the W, X, Y and Z are selected such that the
resulting compounds are asymmetrical;
or a pharmaceutically acceptable salt thereof.
2. A compound of the formula:
##STR4##
3. A compound of the formula
##STR5##
wherein: R=C.sub.1 -C.sub.5 alkyl;
W and X are each, independently of the other, selected from the group
consisting of hydrogen, chloro and fluoro;
one of Y and Z is selected from the group consisting of hydrogen, chloro,
fluoro, methyl, methoxyl and methylthio and the other is selected from the
group consisting of hydrogen, chloro and fluoro;
with the proviso that the W, X, Y and Z are selected such that the
resulting compounds are asymmetrical;
or a pharmaceutically acceptable salt thereof.
4. A compound of the formula
##STR6##
5. A compound of the formula
##STR7##
wherein R=C.sub.1 -C.sub.5 alkyl;
W and X are each, independently of the other, selected from the group
consisting of hydrogen, chloro and fluoro;
one of Y and Z is selected from the group consisting of hydrogen, chloro,
fluoro, methyl, methoxyl and methylthio and the other is selected from the
group consisting of hydrogen, chloro and fluoro;
with the proviso that the W, X, Y and Z are selected such that the
resulting compounds are asymmetrical;
or a pharmaceutically acceptable salt thereof.
6. A compound of the formula:
##STR8##
7. A compound of the formula:
##STR9##
wherein R=C.sub.1 -C.sub.5 alkyl;
W and X are each, independently of the other, selected from the group
consisting of hydrogen, chloro and fluoro;
one of Y and Z is selected from the group consisting of hydrogen, chloro,
fluoro, methyl, methoxyl and methylthio and the other is selected from the
group consisting of hydrogen, chloro and fluoro;
with the proviso that the W, X, Y and Z are selected such that the
resulting compounds are asymmetrical;
or a pharmaceutically acceptable salt thereof.
8. A compound of the formula:
##STR10##
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a novel process for the synthesis of certain
chiral spirofluorenehydantoins, which may be used in the treatment of
complications arising from diabetes mellitus. The invention also relates
to novel intermediate compounds, which are integral to the claimed
process.
2. Description of Related Art
Racemic and the R and S enantiomers of certain chiral
spirofluorenehydantoins have previously been reported to be aldose
reductase inhibitors and thus of value in controlling complications
arising from diabetes mellitus (e.g., diabetic cataracts and neuropathy).
Reference is made to commonly assigned U.S. Pat. No. 4,864,028 (York) for
further background in this regard. The entire contents U.S. Pat. No.
4,864,028 relating to the utility, structure and synthesis of such chiral
spirofluorenehydantoins are hereby incorporated in the present
specification by reference.
Methods of obtaining enantiomerically pure forms of chiral hydantoins have
been described previously. Prior methods have involved resolution using
the resolving agent brucine, or asymmetric synthesis using a method
similar to a procedure described in Sarges, et al., J. Orq. Chem., 47:4081
(1982). The present inventors have found that the R and S enantiomers of
certain substituted spirofluorenehydantoins, such as 2,7-
difluoro-4-methoxyspiro[9H-fluorene-9,4'imidazolidine]-2'5'-dione, cannot
be obtained via such prior methods. There is, therefore, a need for a
method of synthesizing these enantiomers. The present invention is
directed to fulfilling this need. More particularly, the method of this
invention provides for the synthesis of the pure R and S enantiomers of
the subject compounds.
SUMMARY OF THE INVENTION
The present invention provides a method for the synthesis of the R and S
enantiomers of chiral spirofluorenehydantoins of the structure:
##STR1##
wherein: W and X are each, independently of the other, selected from the
group consisting of hydrogen, chloro and fluoro;
one of Y and Z is selected from the group consisting of hydrogen, chloro,
fluoro, methyl, methoxyl and methylthio and the other is selected from the
group consisting of hydrogen, chloro and fluoro;
with the proviso that W, X, Y and Z are selected such that the substituted
pattern does not result in a symmetrical molecule;
and pharmaceutically acceptable salts thereof. The compounds are prepared
from the corresponding fluorenones.
The reaction scheme may be summarized as involving the following five
steps:
##STR2##
The process comprises condensing the fluorenone (I) with an amine,
preferably benzylamine, to form the imine of structure (II), which is then
deprotonated and acylated at C-9 with a lower alkyl chloroformate. In situ
hydrolysis of the resulting imine provides the amino acid ester of
structure (III), which is then resolved to provide the R and S amino acid
esters (IV) and (V), each of which is then reacted with a source of
cyanate to form the R and S urea esters (VI) and (VII), which are each
then cyclized to the spirofluorenehydantoins (VIII) and (IX). The
invention also relates to the novel intermediate compounds of structures
(IV), (V) (VI) and (VII).
DETAILED DESCRIPTION OF THE INVENTION
In words relative to the above schematic representations, the five-step
synthesis of the R and S enantiomers of the subject compounds is described
in greater detail below.
The starting fluorenones (I) may be synthesized according to known
procedures, for example the procedures described in U.S. Pat. No.
4,864,028, or procedures otherwise known to those skilled in the art. The
initial step of the synthesis, conversion of (I) to the imine (II) by
reaction with a glycine ester or a substituted or unsubstituted
benzylamine, preferably benzylamine, may be carried out in an inert,
anhydrous solvent, such as an aromatic hydrocarbon (e.g. benzene,
toluene), an ether (e.g., tetrahydrofuran, dioxane, diethyl ether,
1,2-dimethoxyethane), or a halogenated solvent such as methylene chloride.
The reaction is preferably carried out under conditions wherein the water
is removed from the reaction mixture either azeotropically (e.g., with
benzene or toluene) or by the addition of a dehydrating agent such as
titanium tetrachloride. Higher yields of the desired imine are obtained
using titanium tetrachloride as the dehydrating agent. The temperature for
the reaction can be in the range of -1O.degree. C. to 15.degree. C. Above
15.degree. C. the yield of the desired imine (II) is significantly
reduced. The preferred temperature is in the range of 0.degree. C. to
15.degree. C. The molar ratio of ketone, amine and titanium tetrachloride
is not critical. It can range from theoretical (1:1:0.5) to 1:4:0.75, with
an added base such as a tertiary amine (e.g., triethylamine) to neutralize
the hydrogen chloride produced as a by-product in the reaction or during
isolation (e.g., four moles of base per mole of titanium tetrachloride).
If desired, an excess of the amine reactant itself can be used as the base
for neutralization of the hydrogen chloride.
The second step of the five-step sequence comprises deprotonation of (II)
at the benzylic position to form a delocalized anion which is then
acylated and hydrolyzed. The deprotonation is usually carried out at a
temperature of -70.degree. C. to 45.degree. C. using a base such as
butyllithium, lithium diisopropylamide, or sodium hydride in an inert,
anhydrous solvent, such as an aromatic hydrocarbon (e.g., benzene,
toluene) or an ether (e.g. tetrahydrofuran, dioxane, diethyl ether,
1,2-dimethoxyethane) optionally containing a polar cosolvent (e.g.,
N,N,N',N'-tetramethylethylenediamine (TMEDA) or hexamethylphosphoramide
(HMPA)). The preferred combination is sodium hydride in tetrahydrofuran at
a temperature of 30.degree. C. to 45.degree. C. Under these conditions
deprotonation is judged to be complete when the evolution of hydrogen gas
ceases. Generally, a 10% to 30% excess of the base is employed to ensure
complete deprotonation. The reaction mixture is then cooled to 0.degree.
C. to 15.degree. C. and a two to four-fold molar excess of an alkyl
chloroflormate is added. Methyl chloroformate is preferred, though any
C.sub.1 to C.sub.5 alkyl chloroformate can be used. The reaction mixture
is then stirred for a period of 30 minutes to 2 hours while warming to
room temperature. After this period of time, the mixture is again cooled
to 0.degree. C. to 15.degree. C. and aqueous hydrochloric acid is added to
hydrolyze the imine intermediate to yield the desired compound (III). In
principle, any strong mineral acid (e.g. sulfuric acid or nitric acid)
would be sufficient. The product is conveniently isolated by extraction
into aqueous acid followed by neutralization and filtration.
The third step of the sequence is the resolution of (III) to provide the
R(+) and S(-) enantiomers, (IV) and (V) respectively. This can be
accomplished by a number of methods known to those skilled in the art,
including diasteriomeric salt formation with an acid such as L-tartaric
acid, conversion to diasteriomeric amides followed by chemical or
chromatographic separation and hydrolysis, or chiral chromatography. The
preferred method is by use of a Chiralcel OF column such as that described
in Okamoto, et al., J. Chromatogr, 363:173 (1986), and a mixed solvent
system consisting of hexane and isopropanol, preferably in the ratio of 2
to 1.
The fourth and fifth steps of the synthesis are carried out on enantiomer
(IV) or (V) depending on which enantiomer of the spirofluorenehydantoin is
desired. Proceeding with (IV) provides the R(+) enantiomer (VIII), while
the S(-) enantiomer (IX) is obtained from (V).
In either case, in the fourth step of the synthesis, the R(+) or S(-) amino
acid ester, (IV) or (V) respectively, is reacted with cyanate (sodium or
potassium salts are preferred) in a suitable organic acid, preferably
acetic acid, at 45.degree. C. to 1OO.degree. C. for 15 minutes to 1 hour.
At a temperature of 6020 C., a reaction time of 30 minutes should be
sufficient. The product is conveniently isolated by diluting the reaction
mixture with ice water and collecting the product by filtration. At least
a 1:1 ratio of the cyanate to the amino acid ester is required for high
yields; a two to three-fold excess of cyanate is not detrimental.
In the fifth and final step of the synthesis, a mixture of the R(+) or S(-)
urea ester (VI or VII), and an inorganic base such as potassium carbonate
is stirred in a solvent such as methanol or ethanol at a temperature in
the range of 0.degree. C. to 45.degree. C. Generally, the molar ratio of
the base to urea ester is in excess of 1:1, ranging from 1:1 to 3:1.
Cyclization occurs at such a rate that the reaction is complete after 30
minutes at room temperature in methanol. The progress of the reaction can
be conveniently monitored using thin layer chromatography on silica gel
plates with a methanol/methylene chloride solvent mixture. The R(+) or
S(-) spirofluorenehydantoin product ((VII) or (VIII) respectively) is
easily isolated by solvent evaporation and addition of dilute mineral acid
to the residue, at which point the product can be collected by filtration.
The synthesis of the present invention is further illustrated by the
following examples, wherein a specific embodiment of the invention is
described in detail. However, it should be understood that the invention
is not limited to the specific details of these examples.
EXAMPLE 1
N-(2,7-Difluoro-4-methoxyfluoren-9-ylidene)benzylamine (II)
Titanium tetrachloride (0.127 mol, 127 mL of a 1.0 M methylene chloride
solution) was added dropwise over a 15 minute to a mechanically stirred
suspension of 2,7-difluoro-4-methoxyfluorenone (I) (50.0 g, 0.203 mol) and
benzylamide (81 g, 0.76 mol) in methylene chloride (1 L) under nitrogen,
keeping the temperature below 15.degree. C. The mixture was stirred for 30
min while warming to 24.degree. C., and then filtered through a pad of
Florisil, washing with diethyl ether (4 L). The filtrate was concentrated
to 500 mL and diluted with hexane (500 mL). The precipitated yellow imine
was collected by filtration and combined with second and third crops
obtained by concentration of the mother liquor to provide a total of 64 g
(94%) of (II) as mixture of geometric isomers: IR (KBr) 1648, 1617, 1603,
1592, 1469, 1452, 1321, 1294 cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3, 200
MH.sub.z).delta.7.95-6.40 (m, 10 H), 5.26 and 5.27 (singlets, total 2 H),
3.94 and 3.96 (singlets, total 6 H).
EXAMPLE 2
(35)-9-Amino-2,7-difluoro-4-methoxyfluorene-9-carboxylic acid methyl ester
(III)
The imine (II) (30 g, 90 mmol) was added in portions over a 5 minute period
to a mechanically stirred suspension of hexane washed sodium hydride (0.11
mol, 4.5 g of a 60% oil dispersion) in anhydrous tetrahydrofuran (300 mL)
(distilled from lithium aluminum hydride) at 45.degree. C. under nitrogen.
After 40 minutes, the mixture was cooled to 10.degree. C. and a solution
of methyl chloroformate (0.27 mol, 21 mL) in tetrahydrofuran (40 mL) was
added, keeping the temperature below 12.degree. C. The reaction mixture
was stirred for 1 hour while warming to 24.degree. C., then cooled to
10.degree. C., quenched with 100 mL of 1 M aqueous hydrochloric acid, and
stirred (to 24.degree. C.) for 1 hour. The mixture was diluted with 500 mL
of 1:1 ether/hexane and the amine hydrochloride was extracted with 1 M
aqueous hydrochloric acid. The aqueous solution was neutralized using
sodium bicarbonate and the precipitated product was collected by
filtration. The solid was dissolved in ethyl acetate (800 mL) and the
solution was dried over MgSO.sub.4, decolorized with Norit A, filtered
through Celite, and concentrated. The residue was triturated with ether
and then recrystallized from ethyl acetate/hexane to provide 20.7 g (76%)
of III: mp 153.degree.-155.degree. C. The mother liquor was concentrated
and the residue chromatographed on silica gel using a gradient of pure
methylene chloride to 5% methanol in methylene chloride to give an
additional 1.6 g (6%) of material. IR (KBr) 3389, 3317, 1733, 1598
cm.sup.-1 ; .sup.1 H NMR (CDCl.sub.3,200 MHz).delta.7.90 (dd, 1 H,J=5.2,
8.5 Hz), 7.18 (dd, 1H,J=2.4, 8.3 Hz), 7.04 (ddd, 1 H, J=2.5, 8.4, 9.1 Hz),
6.84 (dd, 1 H, J=2.1, 7.8 Hz), 6.66 (dd, 1 H, J=2.0, 11.1 Hz), 3.97 (s, 3
H), 3.60 (s, 3 H), 2.25 (bs, 2 H); MS m/z 305 (M+), 246 (base peak).
Analysis for C.sub.16 H.sub.13 F.sub.2 NO.sub.3. Calcd: C,62.95; H, 4.29;
N, 4.29. Found: C, 62.84; H, 4.10; N, 4.53.
EXAMPLE 3
Chromatographic resolution of (III)
The chromatographic resolution of III was accomplished on a preparative
scale using a Chiralcel OF column and 2:1 hexane/isopropanol. Twenty-seven
grams of each enantiomer were provided from 100 grams of the racemic
material. The first eluted isomer (IV) had a rotation in methanol of
+1.14.degree., while the second eluted isomer (V) had a rotation of
-1.26.degree..
EXAMPLE 4
R-(+)-2,7-Difluoro-4-methoxy-9-ureidofluorene-9-carboxylic acid methyl
ester (VI)
A mixture of R-(+)-9-amino-2,7-difluorofluorene-9-carboxylic acid methyl
ester (IV) (10.0 g, 32.8 mmol) and sodium cyanate (2 eq, 4.4 g) in acetic
acid (100 mL) was heated at 60.degree. C. for 30 minutes. The mixture was
then diluted with ice-water (800 mL) and the solid was collected by
filtration, washing with water, and air dried to provide 11.4 g (100%) of
VI: mp 252.degree.-254.degree. C.; IR (KBr) 3449, 3381, 1728, 1716, 1687
cm.sup.-1 ; .sup.1 H NMR (DMSO-d.sub.6, 200 MHz) .delta.7.86 (dd, 1 H,
J=5.3, 8.5 Hz), 7.50 (dd, 1 H, J=2.6, 9.0 Hz), 7.26 (m, 2 H), 7.12 (dd, 1
H, J=2.2, 8.5 Hz), 7.04 (dd, 1 H, J=2.2, 11.8 Hz), 5.75 (s, 2 H), 3.98 (s,
3 H), 3.56 (s, 3 H); MS m/z 348 (M+), 246 (base peak);
[.alpha.].sub.D.sup.25 =+5.17.degree.(c=0.5, methanol).
Analysis for C.sub.17 H.sub.14 F.sub.2 N.sub.2 O.sub.4. Calcd: C, 58.62; H,
4.05; N, 8.04. Found: C, 58.55; H, 3.66; N,7.94.
EXAMPLE 5
S-(-)-2,7-Difluoro-4-methoxy-9-ureidofluorene-9-carboxylic acid methyl
ester (VII)
A mixture of S-(-)-9-amino-2,7-difluorofluorene-9-carboxylic acid methyl
ester (IV) (14.0 g, 45.9 mmol) and sodium cyanate (2.2 eq, 6.2 g) in
acetic acid (140 mL) was heated at 60.degree. C. for 30 minutes. The
mixture was then poured into water (1 L) and the solid was collected by
filtration, washing with water, and air dried. This run plus a second run
on 10 g of IV provided a total yield of 27 g (99%) of VII: mp
252.degree.-256.degree. C.; IR (KBr) 3450, 3381, 1728, 1716, 1687
cm.sup.-1 ; .sup.1 H NMR (DMSO-d.sub.6, 200 MH2).delta.7.85 (dd, 1 H,
J=5.3, 8.5 Hz), 7.49 (dd, 1 H, J=2.5, 9.0 Hz), 7.25 (m, 2 H), 7.11 (dd, 1
H, J=2.2, 8.5 Hz), 7.03 (dd, 1 H, J=2.2, 11.6 Hz), 5.75 (s, 2 H), 3.96 (s,
3 H), 3.55 (s, 3 H); MS m/z 348 (M+), 246 (base peak);
[.alpha.].sub.D.sup.25 =-7.96.degree. (c=0.5, methanol).
Analysis for C.sub.17 H.sub.14 F.sub.2 N.sub.2 O.sub.4. Calcd: C, 58.62; H,
4.05; N, 8.04. Found: C, 58.60; H, 4.04; N, 7.88.
EXAMPLE 6
R-(+)-2,7-Difluoro-4-methoxyspiro[9H-fluorene-9,4'-imidazolidine]-2',5'-dio
ne (VIII)
A suspension of R-(+)-2,7-difluoro-4-methoxy-9-ureidofluorene-9-carboxylic
acid methyl ester (VI) (9.6 g, 27.6 mmol) and potassium carbonate (9.6 g)
in methanol (200 mL) was stirred at room temperature for 30 minutes. The
methanol was then evaporated and the residue was acidified with aqueous 1
M hydrochloric acid and filtered, washing with water. The solid was
dissolved in warm ethyl acetate, dried over MgSO.sub.4, treated with Norit
A, filtered through celite, and concentrated. The material so obtained,
when combined with that from 3 similar runs, was first leached with
acetonitrile, filtered at 10.degree. C., and then recrystallized from
acetonitrile/tetrahydrofuran to provide first and second crops of 18.1 and
2.2 g, respectively. The yield for the conversion of 28 g of VI to VIII in
four runs was 80%. mp 300.degree.-304.degree. C.; IR (KBr) 3430, 2735,
1787, 1731 cm.sup.-1 ; .sup.1 H NMR (DMSO-d.sub.6, 200 MHz).delta.11.28
(s, 1 H, exchangeable), 8.64 (s, 1 H, exchangeable), 7.86 (dd, 1 H, J=5.3,
8.4 Hz), 7.43 (dd, 1 H, J=2.4, 8.6 Hz), 7.28 (ddd, 1 H, J=2.5, 8.1, 8.1
Hz), 7.05 (m, 2 H), 3.98 (s, 3 H); MS m/z 316 (M+),245 (base peak);
[.alpha.].sub.D.sup.25 =14.2.degree. (c=1, methanol).
Analysis for C.sub.16 H.sub.10 F.sub.2 N.sub.2 O.sub.3. Calcd: C, 60.76; H,
3.19; N, 8.86. Found: C, 60.98; H, 3.12; N, 8.87.
EXAMPLE 7
S-(-)-2,7-Difluoro-4-methoxyspiro[9H-fluorene-9,4'-imidazolidine]-2',5'-dio
ne (IX)
A suspension of S-(-)-2,7-difluoro-4-methoxy-9-ureidofluorene-9-carboxylic
acid methyl ester (VII) (27.0 g, 77.6 mmol) and potassium carbonate (27 g)
in methanol (500 mL) was stirred at room temperature for 30 minutes. The
methanol was then evaporated and the residue was acidified with aqueous 1
M hydrochloric acid and filtered, washing with water. After air drying
overnight, the solid was dissolved in refluxing ethyl acetate (800 mL),
dried over MgSO.sub.4, treated with Norit A, and filtered through celite.
Solvent removal left 24.3 g of crude material which was leached with
acetonitrile and filtered at 0.degree. C. The acetonitrile filtrate was
evaporated and the residue (2.5 g) was chromatographed on silica gel using
first 25% and then 50% ethyl acetate in hexane to provide additional
material which was combined with that obtained by filtration at 0.degree.
C. Recrystallization from acetonitrile/tetrahydrofuran provided first and
second crops of 15.5 and 5 g, respectively, for a total yield of (IX) of
20.5 g (84%). mp 300.degree.-304.degree. C.; IR (KBr) 3430, 2735, 1787,
1731, 1602, 1316 cm.sup.-1 ; .sup.1 H NMR (DMSO-d.sub.6, 200
MHz).delta.11.29 (s, 1 H, exchangeable), 8.64 (s, 1 H exchangeable), 7.87
(dd, 1 H, J=5.2, 8.5 Hz), 7.43 (dd, 1 H, J=2.4, 8.5 Hz), 7.28 (bddd, 1 H,
J=2.5, 8.1, 8.1 Hz), 7.05 (m, 2 H), 3.98 (s, 3 H); MS m/z 316 (M+), 245
(base peak); [.alpha.].sup.25 =-13.80.degree. (c=1, methanol). D
Analysis for C.sub.16 H.sub.10 F.sub.2 N.sub.2 O.sub.3. Calcd: C, 60.76; H,
3.19; N, 8.86. Found: C, 60.92; H, 3.09; N. 8.85.
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